The formation of trimolecular complex of processed antigen, MHC class II proteins, and T-cell receptor (TCR) is essential for immune responses to both pathogens and self proteins. Antigens contain multiple determinants, yet only a handful of dominant epitopes are strongly recognized by T-cell in the context of class II, a process called immunodominance. The molecular events that control immunodominance are complex, with both APC and T-cells potentially serving regulatory roles. This study will investigate the role of APC and the processing reactions within these cells in regulating immunodominance. The long term goals of this research are to delineate the role of APC in regulating immune responses and to elucidate the intracellular events which control antigen presentation. Studies to define the molecular and cellular steps which guide epitope selection are included in 3 Specific Aims: 1) Processing reactions within APC modulate the presentation of dominant and subdominant epitopes; 2) dominant and subdominant epitopes are formed and intersect class II antigens in different subcellular compartments; 3) selection of immunodominant epitopes from endogenous antigens is differentially controlled by HLA-DM-dependent and independent pathways. Biochemical, cell biological, and functional approaches will be used to test these hypotheses. Understanding epitope selection and immunodominance may be key to enhancing host pathogen resistance as well as modulating autoimmunity.